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Ophthalmic genetics is concerned with the genetic contribution to ophthalmic disease, including determination of patterns and risks of inheritance, as well as diagnosis, prognosis, and development of treatments for genetic abnormalities. Information on the genetics of particular inherited diseases and the availability of genetic testing are available from various internet websites, including those maintained by the National Center for Biotechnology Information [www.ncbi.nlm.nih.gov] and the Gene Test Organization [www.genetest.org].

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Abnormalities of Nuclear or Mitochondrial DNA

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A great number of disorders with ophthalmic manifestations are transmitted in characteristic hereditary patterns through many generations, generally being attributable to deletions, mutations, and/or duplications of small segments of specific chromosomes of nuclear DNA or the circular DNA of mitochondria. Autosomal dominant disorders include neurofibromatosis type 1, tuberous sclerosis, Best vitelliform macular dystrophy, von Hippel–Lindau disease, autosomal dominant optic atrophy, most cases of multifocal retinoblastoma, and some cases of retinitis pigmentosa. Autosomal recessive disorders include oculocutaenous albinism, gyrate atrophy, xeroderma pigmentosum, and some cases of retinitis pigmentosa. X-linked recessive disorders include red-green color blindness, X-linked retinoschisis, ocular albinism, Norrie disease, some cases of retinitis pigmentosa, and most cases of choroideremia. Matrilineal inheritance is characteristic of abnormalities of mitochondrial DNA, such as the point mutations that cause Leber's hereditary optic neuropathy (LHON). Other mitochondrial disorders, in which the characteristic ophthalmic manifestations are chronic progressive external ophthalmoplegia (CPEO) and pigmentary retinopathy, may also be caused by point mutations of mitochondrial DNA, but also may be caused by large deletions of mitochondrial DNA such as in the Kearns–Sayre syndrome, or mutations of nuclear DNA causing abnormalities of mitochondrial function and inherited with an autosomal dominant or autosomal recessive pattern.

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Some abnormalities of nuclear or mitochondrial DNA, for example in some mitochondrial disorders, are rarely transmitted through more than one generation, because the severity of the disorder resulting from a small or more extensive genetic defect limits lifespan or reproductive capability. Occasionally, disease due to a genetic abnormality is not transmitted because the genetic abnormality is confined to somatic cells without being present in the germ cells, for example, most cases of unifocal retinoblastoma (see Chapter 10).

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Chromosomal Abnormalities

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In most disorders with ophthalmic manifestations that clearly have a genetic basis but are rarely transmitted through more than one generation, the genetic abnormality is a major or complete loss or duplication of one or more chromosomes involving numerous genes. Due to the absence of half the normal complement of genes associated with a particular chromosome in cases with complete chromosomal deletions and to the presence of 50% more than the normal complement of genes associated with a particular chromosome in cases with complete chromosomal duplications, affected individuals characteristically have multiple morphological abnormalities, frequently prompting chromosomal analysis during infancy or early childhood. They are frequently sterile or unsuccessful in reproducing. In most cases, the abnormal complement of chromosomes can be identified by karyotyping.

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